Current Pharmaceutical Design - Volume 18, Issue 7, 2012

Sigma (σ ) receptor history started in 1976 when Martin et al. proposed the σ opioid receptors (“ σ-opioid”) to account for the psychotomimetic effects that the benzomorphan SKF-10,047 (N-allylnormetazocine) caused in the chronic spinal dog model and which were blocked by the opioid antagonist naloxone [1]. Later Su et al. identified a binding site which was labeled by [3H]-SKF-10,047 [2] but which was insensitive to naloxone and naltrexone. This finding led to the hypothesis that the protein identified by Su and co-workers was not the - opioid receptor proposed by Martin, so that the name of the binding site was changed to the ‘ receptor’ to distinguish it from the opioid receptor. Evidence that SKF-10,047 and other benzomorphans displayed high affinity for the phencyclidine (PCP) site at the NMDA receptor, and conversely that PCP displayed affinity for the receptor, led to confusion so that sites named PCP/ were introduced for a while. However, subsequent ligand binding studies dispelled this confusion and receptors were finally considered as non-opioid, non-PCP brain receptors. The availability of more ligands led in the early 1990s to the identification of two subtypes of receptors, namely 1 and 2, and soon thereafter the 1 subtype was cloned from guinea pig liver first and from mouse and human cells later [3,4]. The 1 receptors displayed high homology among species but no homology with other known mammalian proteins. Several structures have been proposed for 1 receptors and the most accepted model today shows that the 1 subtype is made of three hydrophobic regions, two of which are transmebrane-spanning segments with the NH2 and COOH termini on the same side of the cell compartment. The binding sites within this subtype have also been identified and several pharmacophoric models have been built for the 1 subtype with the early model proposed by Glennon and co-workers being among the most inspiring [5]. In recent studies two endogenous 1 ligands have been proposed: D-erythro-sphingosine [6] and N,Ndimethyltryptamine (DMT) with the latter being controversial [7,8]. Thorough efforts have been directed towards the elucidation of the signaling mechanism but more studies are still needed to clarify the roles and pathways activated by this subtype. The association of the 1 subtype with G-protein coupled receptors has been finally ruled out, whereas it has been extensively shown that 1 is involved in the regulation of Ca2+ level via IP3 receptors on the endoplasmic reticulum (ER) where a chaperone function for the cross-talk between the ER and mithocondria has been suggested [9]. In addition, 1 receptor modulation of distinct K+ channels and NMDA receptor-coupled ion channels have been demonstrated. All the above actions, together with the involvement in cell lipid compartmentalization suggested for this subtype, give good reason for a role of 1 proteins in cell proliferation. 1 Receptors have been shown to modulate a number of central neurotransmitter systems, and this evidence together with the early findings that several antipsychotic drugs bind with high affinity to 1 subtypes have linked these proteins to important brain functions since their proposal. Increasing evidence implicates this subtype in pathologies such as anxiety, depression, schizophrenia, drug addiction, Alzheimer's disease and movement disorders (such as Parkinson's disease and juvenile amyotrophic sclerosis which has been recently shown to be caused by a mutation to the 1 gene [10]). Noteworthy roles in neuroprotection and neuroplasticity have been suggested for this subtype: 1 ligands protect against brain ischemia and potentiate neurite outgrowth [11,12]. Pharmacological studies and behavioural models for certain CNS diseases have shed light to promising ligands some of which have entered clinical trials. The availability of 1 knockout mice, which are viable and fertile, but which show a difference from the wild-type animals when challenged in behavioural experiments, will likely help to better understand 1 involvement in the CNS [13]. Although initial research was focused on receptors within the CNS, it has been shown that both subtypes are present in peripheral organs at least with the same density as in the CNS, and they are over-expressed in a variety of peripheral and brain human tumors. This evidence has prompted researchers to develop radioligands for the diagnosis of tumors for PET and SPECT analyses with encouraging results which have been recently reviewed in detail [14,15]....

The σ receptors are regarded as unique binding sites, distinct from opiate and PCP receptors and implicated in higher brain function. They were classified into l and 2 subtypes, the former was cloned from rodent and human tissues while the latter has not yet been fully characterized. Although the precise mechanism of the functional response of receptors is still uncertain, it has been accepted that they can modulate a number of central neurotransmitter systems, including glutamate/NMDA, serotonergic, dopaminergic, noradrenergic routes, as well as some other signaling pathways (e.g. neurotrophin and growth factor signaling) which are seemingly important for the brain function. In accordance with their modulatory role, receptor ligands have been proposed to be useful in several therapeutic areas such as schizophrenia, depression and anxiety, amnesic and cognitive deficits, drugs of abuse. The present review summarizes the findings related to the pharmacological effects and potential activity of receptor ligands from behavioral models predictive of some neuropsychiatric disorders.

Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as schizophrenia and psychotic depression. The drugs currently used to treat cognitive impairment have significant limitations, ensuring that the search for more effective therapies remains active. Endoplasmic reticulum protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil and neurosteroids. Among SSRIs, fluvoxamine, a potent sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors. Sigma-1 receptor agonists greatly potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia is significantly improved by sub-chronic administration of sigma-1 receptor agonists such as fluvoxamine, SA4503 (cutamesine) and donepezil. This effect is antagonized by co-administration of NE-100. A positron emission tomography (PET) study using the specific sigma-1 receptor ligand [11C]SA4503 demonstrates that fluvoxamine and donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on sigma-1 receptor agonists as potential therapeutic drugs for the treatment of cognitive impairment in schizophrenia and psychotic depression.

Since their proposal in 1976, sigma (σ) receptors have been increasingly implicated in the pathophysiology of virtually all major central nervous system (CNS) disorders, including anxiety, depression, schizophrenia, and drug addiction. Due to their involvement in motor function and higher cognitive function,σ receptors have also been implicated in movement disorders (such as Parkinson's disease) and memory deficits (including Alzheimer's disease). In most cases the precise mechanism(s) linking σ receptors to CNS disease are unknown or yet to be fully elucidated. However, many σ ligands have shown promise in pharmacological studies and animal models of the aforementioned diseases, and some have entered clinical trials. This review will assess the validity of receptors as a target for various CNS diseases based on evidence from animal models of human diseases, preclinical studies in humans, and full clinical trials.

Drug abuse is currently a large economic and societal burden in countries around the globe. Many drugs of abuse currently lack adequate therapies aimed at treating both the addiction and negative complications often associated with their use. Sigma-1 receptors were discovered over 30 years ago and have recently become targets for the development of pharmacotherapies aimed at treating substance abuse and addiction. In vivo preclinical studies have revealed that sigma receptor ligands are able to ameliorate select behavioral effects of many drugs of abuse including cocaine, methamphetamine, ethanol and nicotine. In addition, recent studies have begun to elucidate the mechanisms by which sigma-1 receptors modulate the effects of these drugs on neurotransmission, gene regulation and neuroplasticity. Overall, these recent findings suggest that compounds targeting sigma-1 receptors may represent a potential new class of therapeutics aimed at treating drug abuse. Future studies involving clinical populations will be critical for validating the therapeutic potential of sigma-1 receptor ligands for the treatment of substance abuse.

The sigma-1 receptor is a 26 kDa endoplasmic reticulum resident membrane protein that has been shown to have chaperone activity in addition to its promiscuous binding to pharmacological agents. Ligand binding domain(s) of the sigma-1 receptor have been identified using the E. coli expressed and purified receptor protein and novel radioiodinated azido photoaffinity probes followed by proteolytic and chemical cleavage strategies. The outcome of these experiments indicates that the sigma-1 receptor ligand binding regions are formed primarily by juxtaposition of its second and third hydrophobic domains, regions where the protein shares considerable homology with the fungal enzyme, sterol isomerase that is essential for the biosynthesis of ergosterol. Data indicate that these hydrophobic steroid binding domain like (SBDL) regions on the sigma-1 receptor are likely to interact selectively with N-alkyl amines such as the endogenous sphingolipids and with synthetic N-alkylamines and N-aralkylamines derivatives. A proposed model for the sigma-1 receptor is presented.

The existing pharmacophore models for 1 receptor ligands are summarized. A common feature of these models is a basic amino group surrounded by different hydrophobic structural elements. The development of novel spirocyclic 1 receptor ligands (e.g. 3, 4) is based on these models. Enlargement of the distance between the basic amino group and the “Primary Hydrophobic Region ” by attachment of the amino group at the cyclohexane ring (9, 10) did not lead to increased 1 affinity. However, introduction of an additional aryl moiety (12, 17) resulted in very potent 1 receptor ligands. The high affinity of these compounds is explained by interaction of the additional aryl moiety with a previously unrecognized hydrophobic pocket of the 1 receptor protein. The promising 1 affinity and selectivity of the spirocyclic piperidine 3 led to the fluorinated PET-tracers [18F]18 and [18F]19 with excellent 1 receptor affinity, receptor selectivity, pharmacokinetic and neuroimaging properties.

Although several pieces of information are still missing about sigma-2 ( 2) receptor, the production of high affinity 2 receptor ligands allowed important acquisitions. Morphans such as CB64D and CB184 were the first truly 2-selective ligands synthesized, and their use in cell cultures highlighted the relationship between 2 receptors and cell proliferation, shedding light on important diagnostic and therapeutic potentials with which 2 ligands are endowed. The most significant classes of compounds are herein discussed. The design and Structure-Affinity Relationship studies (SAfiR) of 2 receptor ligands belonging to the classes of morphans, indoles (siramesine analogues), granatanes, flexible benzamides and N-cyclohexylpiperazines are reported, together with the biological results which these compounds provided giving a crucial contribution to the 2 receptor research. The pharmacophore models which were generated on the basis of different classes of the 2 ligands and the attempts for 2 receptor purification are briefly described.

The renin-angiotensin-aldosterone system (RAAS) exerts a crucial role in the regulation of blood pressure and its pharmacological inhibition is essential to prevent cardiovascular events related to hypertension [1]. This “historical” concept has been recently updated by several knowledge improvements, suggesting that the RAAS might induce a series of “pleiotropic activities” [2]. This system has been shown to trigger intracellular cascades via selective transmembrane receptors in several cell subsets and peripheral tissues [2]. Furthermore, the recent identification of an “intracellular” Renin-Angiotensin System (RAS) has further increased the complexity of the classical hormonal axis. The strong effort of experimental and clinical researches have also highlighted new peptides (such as Angiotensins), receptors and enzymes [3] that might directly regulate inflammatory mechanisms in aging [4]. On the basis of these discoveries, both systemic and intracellular RAS have been investigated to better understand their role in different diseases, such as atherosclerosis and related inflammation. In addition, these studies have contributed to better define novel therapeutic targets and beneficial effects for drugs inhibiting RAAS. Several efficient inhibitory drugs (such as angiotensin-converting enzyme inhibitors [ACEIs], angiotensin II type 1 receptor blockers [ARBs], aldosterone antagonists, and renin inhibitors) have been shown to directly reduce inflammatory and vascular cell activation [5, 6]. Given this emerging background, the present Hot-Topic Issue will update the pleiotropic activities of RAAS and the different strategies targeting its inhibition. Veglio and co-workers discussed the rationale and the possible use of different combinations among RAAS antagonists in certain diseases, such as heart failure, proteinuric nephropathy, and resistant hypertension. Although it should be carefully monitored for safety concerns, an approach characterized by a more complete blockade of the system using RAAS blockers' combinations could be recommended. Stohr and Marx focused on the potential benefits of treatments with RAAS blockers in the prevention of type 2 diabetes mellitus. In their review, authors updated evidence on the contrasting metabolic effects of RAAS inhibitors in humans and mice. Capettini and co-workers discussed on the interesting interactions between RAAS and immunological aspects in aging. RAAS has been shown to modulate the production of reactive oxygen species (ROS) and the release of inflammatory mediators (such as certain cytokines and chemokines), thus potentially regulating the immune response in inflammatory disorders. In particular, the possible role of the counterbalancing anti-inflammatory ACE2/Ang-(1-7)/Mas receptor axis has been updated.

The renin angiotensin aldosterone system (RAAS) inhibitors induce an incomplete blockade of the system at different steps. Recently, the dual RAAS therapy is emerging in clinical practice, although there is a lack of evidence on safety and efficacy for this combination in several cardiovascular diseases. In this review, we evaluated the advantages and disadvantages of dual RAAS blockade in hypertension, proteinuric renal disease, heart failure and ischaemic heart disease. The role of DRIs in combination with ACEI or ARBs is promising, but still needs further studies. On the basis of the clinical outcomes and safety data the recommendations guidelines have not confirmed indications to dual RAAS blockade in essential hypertension treatment, heart failure and ischemic heart disease. Only proteinuric nephropaties and resistant hypertension may represent possible indications to dual RAAS blockade. Actually, rational combinations of either an ACEI or ARB or DRI with other classes of antihypertensives offer best solutions.

ACE inhibitors have established their role in the management of hypertension as well as in the primary and secondary prevention of cardiovascular events. Furthermore, they have proven their role in delaying the worsening of renal function in patients with chronic renal disease. Over the last few years their use to prevent the new onset of diabetes has come to the forefront. Post-hoc analyses of large mutli-center clinical trials such as the Captopril Prevention Project and the Heart Outcomes Prevention Evaluation have suggested that their use may delay or prevent the onset of diabetes. However many of these results are based on secondary analyses and few prospective clinical trials exist. In the two prospective trial so far conducted regarding the use of ACEi and ARB as a means to diabetes prevention the effects of these drugs compared to lifestyle modifications have been minimal and do not yet warrant their use to this effect. While there is strong evidence for modulation the Renin-Angiotensin System in patients with hypertension, coronary heart disease and renal dysfunction the evidence for preventing diabetes remains scarce and will need to be investigated further.

Recent data support the idea that the effects of RAS are not restricted to the cardiovascular and renal systems. Importantly, RAS modulates free radical production and the cellular synthesis of several molecules such as cytokines, chemokines and transcription factors. These functions reflect directly the RAS ability to modulate the cell growth, senescence and migration. Activation of the classic RAS, ACE/Ang II/AT1R, has been strictly related to down regulation of pro-survival genes (Nampt and Sirt3), increase in ROS production and pro-inflammatory cytokines and chemokines release, leading to cell senescence, inflammation and development of autoimmune dysfunctions. However, the new view of RAS, points to the ACE2/Ang-(1-7)/Mas receptor axis as a counter-regulator of the effects of the classic Ang II-mediated effects. This new pathway is not totally elucidated. However, some studies suggest an important role of this novel axis in the control of cytokines release as well as cell migration and synthesis, preventing extra-cellular matrix deposition and cell apoptosis. Classic RAS blockers have been proposed as anti-inflammatory and immunomodulatory agents and some studies suggest a new potential application of RAS blockers in autoimmune diseases. The aim of the present review is to update the novel roles of classical and new RAS components and their possible implication during the physiological aging, in the immune system and inflammation.

Chronic kidney disease has become a major public health problem worldwide mainly as a consequence of the emerging epidemic of hypertension, diabetes, and obesity. It is currently estimated that nearly 15% of the general population has some degree of renal damage, a figure that reaches 50% in at-risk subgroups. Renin-angiotensin-aldosterone system (RAAS) inhibitors represent the agents of choice to control hypertension and reduce urinary albumin excretion, thereby delaying renal function deterioration. Greater blockade of the RAAS either by the combined use of multiple drugs or by supramaximal doses of single agents may provide greater renal protection. Furthermore, it has been proposed especially in the presence of proteinuria. However, at this time there is insufficient evidence to routinely recommend this therapeutic approach in patients with chronic kidney disease. The present article examines the currently available evidence and practical implications of pharmacological disruption of RAAS activity for renal protection.

Renin-Angiotensin-Aldosterone (RAAS) is a hormone system which acts on multiple physiologic pathways primarily by regulating blood pressure and fluid balance, but also by local autocrine and paracrine actions. In pathophysiologic conditions RAAS also contributes to the development of atherosclerosis and its various manifestations, both directly and indirectly through the actions on other systems. RAAS mainly acts as a promoter of atherosclerosis by its action on vessels, and by promoting the developmentt of hypertension, insulin resistance and diabetes, obesity, vascular and systemic inflammation. As RAAS plays a key role in the pathogenesis of cardiovascular diseases, RAAS genes have been extensively studied as candidate genes for atherosclerosis and coronary artery disease. Several polymorphisms of its genes have been found to be in relationship with atherosclerosis and cardiovascular diseases. In this review we will discuss these issues and present the most recent advances about this topic.

Despite the attractiveness of a vaccination strategy for the treatment of high blood pressure, and many decades of research, attempts to translate this strategy to hypertension management have been unsuccessful. Immunization against components of the renin angiotensin system offers the prospect of improved long-term control of hypertension because efficacy does not require daily compliance with oral medication. Moreover, such a strategy may provide therapeutic benefits beyond blood pressure control, such as improved prevention and treatment of heart failure, and cardiovascular, cerebrovascular, and renal disease. However, despite these potential advantages, there are a number of concerns about the safety and efficacy of this approach. Renin immunization demonstrated effective blood pressure reduction in animal models of hypertension but was accompanied by autoimmune disease of the kidney. Moreover, there are theoretical arguments that angiotensin immunization may have limited effectiveness and clinical studies confirmed these limitations. Vaccination against the angiotensin II type 1 receptor is another possible approach but has yet to undergo clinical evaluation. Thus, the role of vaccination against renin angiotensin system components in hypertension management remains to be established.

Guidelines for the treatment of hypertension allow a wide range of choices to the physicians; however some differences are present about the preferred drugs to start treatment. The most important aim remains an adequate decrease of blood pressure, something not perfectly obtained in the general population, but some classes of anti-hypertensive drugs could show protective effects on cardiovascular events, which are independent from blood pressure levels (the so called effects beyond blood pressure control). In this context antagonists of the renin-angiotensin system may represent an important help for the physicians, keeping in mind the preclinical studies showing the central role of the renin-angiotensin system not only in the regulation of blood pressure but also in the atherothrombotic processes. The demonstration of an additional favourable effect of renin-angiotensin system blockers is not so obvious and frequently debated in the literature. Evidence-based medicine suggests that in patients at moderate/high cardiovascular risk it is difficult to have clear evidence of a specific advantage of some drug classes with respect to the others. However renin-angiotensin system blockers maintain compelling indications in particular cardiovascular situations; in addition analysis of intermediate end points, such as microalbuminuria, left ventricular hypertrophy, and arterial stiffness, gives further support to a drug-based anti-hypertension strategy. Last but not least, the optimal safety profile of these drugs, in particular of angiotensin II receptor blockers and renin inhibitors, allows their use in the very early stage of the hypertensive situation, as suggested by recent clinical trials.